Alzheimer's disease (AD) is the most common cause of dementia after the age of 60. The pathological hallmarks of AD include deposition of amyloid ?-peptide (A?) in neuritic plaques and cerebral blood vessels, neurofibrillary tangles, and loss of neurons. Increasing evidence supports the notion that A? and its precursor play important roles in the pathogenesis of AD. Immunization of mouse models of AD with synthetic A? reduces A? deposits and attenuates their memory and learning deficits. Recent clinical trials, however, were halted due to brain inflammation, presumably induced by T-cell mediated and/or Fc-mediated immune responses. Peripheral administration of antibodies against A? also induced clearance of preexisting amyloid plaques in AD mouse models, indicating that an active T-cell-mediated immune response is unnecessary. Topical application of the F(ab')2 without Fc of antibodies against A? led to clearance of amyloid deposits in an AD mouse model, indicating that non-Fc-mediated mechanisms are involved in the clearance. Although these passive immunization modalities may be effective in treating AD patients without inducing inflammatory responses, such modalities suffer from cerebral hemorrhages and repeated administrations of antibodies, leading to a large financial and physical burden to AD patients. We hypothesize that single chain antibodies (scFvs) against A? are effective and safe in treating AD mouse models. We further hypothesize that A? - hydrolyzing immunoglobulin variable domains (IgVs) are superior to reversibly biding Igs in terms of their A? - clearance efficacy and safety. We proposed to produce catalytic and non-catalytic Ig in the brains of AD model mice via rAAV-mediated gene delivery and compare their efficacy and safety in reducing cerebral A? load and improving behavioral deficits. This study will serve as a proof of principle to demonstrate if expression of catalytic and non-catalytic Igs in the brain safely clears A? deposits and improves learning and memory deficits in an AD mouse model. The Specific Aims of this study are (Aim 1) to express catalytic and non-catalytic Igs in a young AD mouse model and compare their prophylactic efficacy and safety and (Aim 2) to express catalytic and non-catalytic Igs in an aged AD mouse model and compare their therapeutic efficacy and safety. We utilize neuropathological, biochemical, immunological, and behavioral analyses to determine the prophylactic and therapeutic efficacy and safety of the modalities. The long-term goal is to establish the logical basis for developing safe and effective immunotherapy for AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. To date, however, no satisfactory treatments are available for AD. This study will serve as a proof of principle to demonstrate if our novel immune gene therapy modality for A? -catalytic and non-catalytic antibody delivery is effective and safe in treating an animal model of AD.